I evaluated and presented the IMPACT trial which compared the effects of once-daily triple therapy versus once-daily dual therapy on COPD exacerbations in afflicted patients. While this trial displayed strong evidence favoring triple therapy over dual therapies, certain methodologies may have inflated the difference.

1. Journal Club Presentation by Jefferson Pike
May 23, 2018

2. 2
Introduction
• Sponsors + Affiliates: GSK,
Perelman School of Medicine,
of Pennsylvania, Temple
of Medicine
• Objective: Compare the effects
of once-daily triple therapy
daily dual therapy on COPD
in afflicted patients.
• Rationale: The advantage of
triple therapy with LABA, LAMA,
inhaled glucocorticoid is
compared to dual therapy with
the above agents.

3. 3
Introduction
• Sponsors + Affiliates: GSK,
Perelman School of Medicine,
of Pennsylvania, Temple
of Medicine
• Objective: Compare the effects
of once-daily triple therapy
daily dual therapy on COPD
in afflicted patients.1
• Rationale: The advantage of
triple therapy with LABA, LAMA,
inhaled glucocorticoid is
compared to dual therapy with
the above agents.
COPD Severity Groups, from GOLD 2017 Guidelines2

4. 4
Introduction
• Sponsors + Affiliates: GSK,
Perelman School of Medicine,
of Pennsylvania, Temple
of Medicine
• Objective: Compare the effects
of once-daily triple therapy
daily dual therapy on COPD
in afflicted patients.
• Rationale: The advantage of
triple therapy with LABA, LAMA,
inhaled glucocorticoid is
compared to dual therapy with
the above agents.1
COPD Severity Groups, from GOLD 2017 Guidelines2

5. Methods:
Study Design1
5
Phase III
Multicenter52 week Double blind Parallel Group
ICS + LAMA + LABA ICS + LABA LAMA + LABA
Randomized
Superiority tests

6. Methods – Patients/Subjects1
Inclusion Criteria
• 40+ y.o. AND symptomatic COPD
range, 0 to 40)
AND EITHER:
• FEV1 < 50% predicted normal value
moderate or severe COPD
previous year
OR
• FEV1 50% – 80% predicted normal
moderate or 1+ severe exacerbations
previous year
Exclusion Criteria:
• Pregnancy,
• subjects with a current Dx of asthma,
other respiratory disorders,
• unresolved COPD
exacerbations/pneumonia,
• unstable liver or cardiac disease,
cancer,
• long term oxygen therapy >3 L/min,
• drug/alcohol abuse, contraindications
6

7. Methods – Patients/Subjects1
• N=10,355
• Enrolled patients through 1,200 study centers in 37 different countries from June 2014 through July 2017
• Triple Therapy: N = 4,151
• ICS-LABA: N = 4,134
• LAMA-LABA: N = 2,070
• Age 65.3±8.3
• Female sex: 3,485 (34%)
• BMI: 26.6
• Former smokers: 6,768 (65%; current smokers 35%)
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8. Methods – Treatment Regimens1
8
Triple Therapy (N=4,151) ICS + LABA (N=4,134) LAMA + LABA (N=2,070)
Fluticasone furoate 100 ug Fluticasone furoate 100 ug umeclidinium 62.5 ug
umeclidinium 62.5 ug vilanterol 25 ug vilanterol 25 ug
vilanterol 25 ug
-- Two week run-in period on previous medication regimen --
--One year treatment duration--

9. Primary: Annual rate of moderate to severe exacerbations during treatment of
triple therapy vs. each of the two respective dual therapy treatments (co-
primary analyses).
Secondary:
• Spirometry to assess trough FEV1 and change in SGRQ score
• Time to first moderate or severe COPD exacerbation
• Annual rate of moderate or severe COPD exacerbations and the time to
moderate or severe exacerbations among patients with a blood eosinophil
count of 150+ cells per uL at baseline
• Annual rate of severe exacerbations
Methods – Outcome Measures1
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Mild Exacerbation: “Worsening of symptoms treated with increased albuterol”
Moderate
Exacerbation:
“Exacerbation requiring treatment with antibiotics or systemic
glucocorticoids”
Severe
Exacerbation:
“One resulting in hospitalization or death.”

10. • Intent to Treat population = all patients randomized to study treatment and who received
at least one dose of double-blind medication
• Lost to follow-up:
o Triple Therapy: 21 (<1%)
o ICS-LABA: 25 (<1%)
o LAMA-LABA: 14 (<1%)
• Premature Discontinuation:
o Triple Therapy: 758 (18%)
o ICS-LABA: 1,040 (25%)
o LAMA-LABA: 566 (27%)
• Most common reasons for dropouts:
o Adverse events (~7%)
o Lack of efficacy (~7%)
o Decision by patient or proxy (~7%)• T
Methods – Data Handling1
10

11. Primary endpoint:
• Two-sided 1% significance level
• 90% power
• Negative binomial model with dispersion parameter 0.75
• Truncated Hochberg method with statistical hierarchy to control type I error
Secondary endpoints:
• Event-rate analyses: same as above
• Time-to-Event analyses: Cox Proportional Hazards model
• Truncated Hochberg method to control multiplicity in each block
Methods – Statistics1
11

12. Primary Outcome:
• Rate of moderate or severe exacerbations during treatment:
• ICS – LABA: 1.07 per year
• LAMA – LABA: 1.21 per year
• Triple Therapy: 0.91 per year
• 15% reduction over ICS-LABA (rate ratio 0.85, CI 0.80-0.90, p<0.001
• 25% reduction over LAMA-LABA (rate ratio 0.75, CI 0.70-0.81, p<0.001
According to these results, the rate of moderate-severe COPD exacerbations is
significantly lower in triple therapy vs. either of the dual therapy options.
Methods – Results1
12

13. Secondary Outcomes:
• Time-to-first-exacerbation:
• Hazard ratio for triple therapy v. ICS-LABA was 0.85 (CI 0.80-0.91,
• Hazard ratio for triple therapy v. LAMA-LABA was 0.84 (CI 0.78-0.91,
• Annual rate of moderate or severe exacerbations was lower with triple therapy
regardless of eosinophil count, though greater reduction did occur in pts with
• For pts with < 150 cells/uL:
• Triple therapy: 0.85 (95% CI 0.80-0.91)
• ICS-LABA: 1.06 (95% CI 0.99-1.14)
• LAMA-LABA: 0.97 (95% CI 0.88-1.07)
• For pts with 150+ cells/uL:
• Triple therapy: 0.95 (95% CI 0.90-1.01)
• ICS-LABA: 1.08 (95% CI 1.01-1.14)
• LAMA-LABA: 1.39 (95% CI 1.29-1.51)
Methods – Results1
13

14. Secondary Outcomes (cont’d):
• Annual rates of severe exacerbations:
• Triple therapy 0.13
• ICS-LABA 0.15 (RR with triple: 0.87, p = 0.06, not significant)
• LABA-LAMA 0.19 (RR with triple: 0.66, p<0.001)
• Spirometric outcome of the mean change from baseline in trough FEV1:
• Difference between triple and ICS-LABA = 97 mL (95% CI 85-109, p<0.001)
• Difference between triple and LAMA-LABA: 54 mL (95% CI 39-69, p<0.001)
• Mean change from baseline in SGRQ score:
• Triple: -5.5
• ICS-LABA: -3.7 (p<0.001 compared to triple)
• LAMA-LABA: -3.7 (p<0.001 compared to triple)
Methods – Results1
14

15. • Higher incidence of pneumonia with ICS
• Triple therapy vs. LAMA-LABA pneumonia risk: Hazard ratio 1.53; 95%
CI 1.22-1.92, P<0.001)
• d/c due to adverse events: 6% for triple therapy, 8% for ICS-LABA, 9%
for LAMA-LABA
• Serious adverse events occurred in: 22% of triple therapy, 21% of GC-
LABA, and 23% of LAMA-LABA.
• Serious pneumonia occurred in 4%, 4%, and 3%, respectively
• Common AE’s included: viral URTI, URTI, pneumonia, bronchitis, oral
candidiasis, influenza, sinusitis, UTI
• No clinically relevant differences in ECG measurements, vital signs, or lab
values.
Safety1
15

16. Once-a-day triple therapy inhaler resulted in significantly
lower rates of moderate to severe COPD exacerbations than
either of the dual therapies, regardless of patient’s initial
blood eosinophil levels.
ICS-LABA combo is superior to LAMA-LABA with regard to
moderate and severe COPD exacerbation rates; findings that
contrast the results of the FLAME trial. 3 They blame the
FLAME methodology that required a 1 mo run-in period on
LAMA therapy.
It is unknown whether the abrupt discontinuation of inhaled
GC’s could have contributed to the finding of a lower rate of
exacerbations in the ICS groups than in the LAMA-LABA
group. Further research is needed.
Conclusion (Authors)1
16

17. 17
Analysis – Strengths
• Large study population
• Robust clinical trial design
• Same molecules and delivery device
used in the comparison of triple and dual
therapies
• Patients used an electronic diary to
swiftly and accurately report AE’s and
exacerbations
• Pneumonia symptoms were carefully
screened and recorded

18. 18
Analysis – Weaknesses
• Key Problem: Some patients
taking inhaled GC’s before
(67%) were randomized to the
LABA group, leading to abrupt
of GC therapy upon study
• COPE study has identified
inhaled-GC cessation to have a
hazard ratio for inducing
over placebo (95% CI 1.1-2.1)4
• This could have exaggerated
of GC therapies over LAMA-

19. 19
Analysis – Weaknesses
Other Weaknesses:
• Patients with prior history of asthma were
included in the study
• 40% of patients were already on triple
therapy previously
• Patient-recorded symptoms are
subjective

20. 20
https://www.fiercepharma.com/pharma/nejm-editorial-slams-design-gsk-s-pivotal-trial-3-1-copd-med-trelegy
https://www.nejm.org/doi/full/10.1056/NEJMe1716802?query=recirc_curatedRelated_article

21. 21
Conclusions
• While single-inhaler combo treatments simplify administration for
patients, methodological issues weaken this study’s claim that triple
therapy is definitively superior to the current first-line standard in group
D: LAMA-LABA.
• Until a landmark COPD trial properly accounts for the various
treatment steps of patients upon enrollment, providers should
maximize LAMA-LABA therapy as tolerated before progressing to
triple therapy with an inhaled glucocorticoid.

22. 22
References
1. Lipson DA, Barnhart F, Brealey N, Brooks J, Criner GJ, Day NC, Dransfield MT, Halpin DMG, Han MK, Jones CE,
Kilbride S, Lange P, Lomas DA, Martinez FJ, Singh D, Tabberer M, Wise RA, Pascoe SJ; IMPACT Investigators.
Once-Daily Single-Inhaler Triple versus Dual Therapy in Patients with COPD. N Engl J Med. 2018 May
3;378(18):1671-1680. doi: 10.1056/NEJMoa1713901. Epub 2018 Apr 18. PubMed PMID: 29668352.
2. From the Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic
Obstructive Lung Disease (GOLD) 2017. Available from: http://goldcopd.org.
3. Wedzicha JA, et al. "Indacaterol-Glycopyrronium versus Salmeterol-Fluticasone for COPD". The New England
Journal of Medicine. 2016. 374(23):2222-2234.
4. van der Valk P, Monninkhof E, van der Palen J, Zielhuis G, van Herwaarden C. Effect of discontinuation of inhaled
corticosteroids in patients with chronic obstructive pulmonary disease: the COPE study. Am J Respir Crit Care
Med. 2002 Nov 15;166(10):1358-63. Epub 2002 Sep 5. PubMed PMID: 12406823.

23. Journal Club Presentation
Jefferson Pike
May, 2018

24. 24
Appendix 1:
Patient Flow
Chart

25. 25
Appendix 2: Patient GOLD Grade1

26. 26
Appendix 3: Patient COPD History1

27. Appendix 4 – Demographics1
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